Primary Sjögren`s syndrome (pSS) is an autoimmune chronic inflammatory disease characterized by lymphoid infiltrations of exocrine glands and increased levels of autoantibodies against the ribonucleoproteins Ro/SSA and La/SSB. Microarray studies have demonstrated increased gene expression of lymphotoxin beta (LTB) in pSS salivary glands. The aim of the present study was to investigate whether single nucleotide polymorphisms (SNPs) in the lymphotoxin alpha (LTA), LTB and tumor necrosis factor (TNF) gene clusters are associated with pSS.

A total of 527 pSS patients and 532 controls participated in the study. All of them were of Caucasian origin from Sweden and Norway. Eleven SNP markers were genotyped and analysed for their association with pSS using single marker logistic regression and for genotypic association with a chi square test. Eight markers showed significant association with pSS. The SNP rs909253 in intron 1 of LTA showed the strongest association with pSS in both the Norwegian cohort (P= 1.3E-03) and the Swedish cohort (P= 2.6E-05). Importantly, the strength of the association increased (P= 1.3E-07) when the two cohorts were analysed together, showing an odds ratio (OR) of 1.59 [95% CI: 1.34  1.89]. When only pSS patients positive for anti-Ro/SSA -La/SSB (n = 381) were compared with the controls, the association with SNP rs909253 was even stronger (P= 4.2E-10, OR 1.82 95% CI: 1.512.20). Some SNPs within this locus were also associated with extraglandular manifestations such as high plasma levels of IgG, hypothyroidism, arthritis and leucopenia in pSS patients. In conclusion, a strong association was found between several SNPs in the LTA gene locus and pSS, some of which lead to amino acid changes. Our data together with previously published reports suggest a direct role for lymphotoxin alpha in the development of pSS. The importance of this finding for the inflammatory processes in pSS needs further investigation.